AG490 ameliorates early brain injury via inhibition of JAK2/STAT3-mediated regulation of HMGB1 in subarachnoid hemorrhage.
AG490 ameliorates early brain injury via inhibition of JAK2/STAT3-mediated regulation of HMGB1 in subarachnoid hemorrhage.
复制标题
AG490通过抑制JAK2/STAT3介导的HMGB1在蛛网膜下腔出血中的调节来改善脑损伤。
DOI：
10.3892/etm.2017.5539
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发表时间：
2018-03
影响因子：
2.7
通讯作者：
Ma XD
中科院分区：
文献类型：
--
作者：
An JY;Pang HG;Huang TQ;Song JN;Li DD;Zhao YL;Ma XD
高迁移率族蛋白1（HMGB 1）是一种经典的损伤相关分子模式，在病理性炎症反应中起重要作用。体外研究表明，Janus激酶2（JAK 2）/信号转导子和转录激活子3（STAT 3）信号通路参与HMGB 1表达的调控，介导炎症反应。因此，本研究的目的是评估JAK 2/STAT 3通路参与蛛网膜下腔出血（SAH）依赖性调节HMGB 1，使用体内大鼠模型。采用血管内穿孔法建立SAH模型。采用免疫印迹、免疫组织化学和免疫荧光法检测SAH后HMGB 1的表达。此外，还观察了SAH后AG 490对JAK 2/STAT 3磷酸化、HMGB 1表达和脑损伤的影响。SAH后JAK 2/STAT 3蛋白磷酸化程度显著升高（P<0.05），HMGB 1蛋白表达水平显著升高（P<0.05）。此外，SAH后胞浆HMGB 1水平表现出初始增加，随后下降到对照水平，而SAH后核HMGB 1水平表现出相反的趋势，初始下降，随后增加。SAH后给予AG 490可显著抑制JAK 2/STAT 3磷酸化（P<0.05），抑制HMGB 1的表达和转位，减少皮质细胞凋亡、脑水肿和神经功能缺损。这些结果表明JAK 2/STAT 3通路参与SAH后HMGB 1的调节。
High mobility group box 1 (HMGB1) is a classic damage-associated molecular pattern that has an important role in the pathological inflammatory response. In vitro studies have demonstrated that the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is involved in the regulation of HMGB1 expression, mediating the inflammatory response. Therefore, the purpose of the present study was to evaluate JAK2/STAT3 pathway involvement in the subarachnoid hemorrhage (SAH)-dependent regulation of HMGB1, using an in vivo rat model. A SAH model was established by endovascular perforation. Western blotting, immunohistochemistry and immunofluorescence were used to analyze HMGB1 expression after SAH. In addition, the effects of AG490 after SAH on JAK2/STAT3 phosphorylation, HMGB1 expression and brain damage were evaluated. The results of the present study demonstrated that JAK2/STAT3 was significantly phosphorylated (P<0.05) and the total HMGB1 protein level was significantly increased (P<0.05) after SAH. In addition, the cytosolic HMGB1 level after SAH demonstrated an initial increase followed by a decrease to the control level, while the nuclear HMGB1 level after SAH demonstrated the opposite trend, with an initial decrease and subsequent increase. AG490 administration after SAH significantly inhibited JAK2/STAT3 phosphorylation (P<0.05), suppressed the expression and translocation of HMGB1, reduced cortical apoptosis, brain edema and neurological deficits. These results demonstrated the involvement of the JAK2/STAT3 pathway in HMGB1 regulation after SAH.
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体内和体外实验性蛛网膜下腔出血神经元早期释放高迁移率族盒 1 (HMGB1)。
影响因子：
9.3
作者：
Sun Q;Wu W;Hu YC;Li H;Zhang D;Li S;Li W;Li WD;Ma B;Zhu JH;Zhou ML;Hang CH
通讯作者：
Hang CH
影响因子：
64.8
作者：
Scaffidi, P;Misteli, T;Bianchi, ME
通讯作者：
Bianchi, ME
影响因子：
8.3
作者：
GARCIA, JH;WAGNER, S;HU, XJ
通讯作者：
HU, XJ
影响因子：
3.8
作者：
Agnello, D;Wang, HC;Ghezzi, P
通讯作者：
Ghezzi, P
影响因子：
2.5
作者：
Li, Dan-Dong;Song, Jin-Ning;Wang, Jun-Feng
通讯作者：
Wang, Jun-Feng